To investigate the mechanisms underlying the expression of allergic contact dermatitis, we compared the characteristics of nickel (Ni)-specific T cell responses in 10 patients with allergic contact dermatitis to Ni and in 10 healthy, nonallergic individuals. CD4+ T cells purified from peripheral blood of both allergic and nonallergic subjects proliferated similarly to NiSO4 in vitro, with the responses mostly restricted to CD4+ CD45RO+ memory T cells. In contrast, Ni-specific CD8+ T cell responses were detected only in allergic patients. Limiting dilution assay confirmed a high frequency of Ni-specific CD4+ T cells in both individual categories, and of Ni-specific CD8+ T cells in allergic patients, but not in nonallergic persons. Ni-specific CD4+ T cell clones prepared from nonallergic subjects displayed lower interferon-gamma and higher interleukin-10 production compared with T cell clones from allergic patients. The T cell skin-homing receptor, cutaneous lymphocyte-associated antigen, was expressed on the large majority of specific CD4+ clones from both the groups. Finally, Ni-specific CD8+ clones prepared from patients also expressed the cutaneous lymphocyte-associated antigen receptor, and released high interferon-gamma and no interleukin-4. In aggregate, the results suggest that the presence of specific CD8+ T cells and a distinct pattern of cytokine release (e.g., an augmented production of interleukin-10) by CD4+ T cells can be important elements in determining whether a hapten induces allergy or a silent immune response.